The goal of this NRSA proposal is to use new approaches to further investigate the role of lipid signaling in olfactory signal transduction. Recent findings have rekindled interest in the possible involvement of phospholipid signaling in vertebrate olfactory transduction. The research project builds on indirect evidence from previous studies that the phospholipid substrates and products of phosphoinositide 3-kinase (PI3K) metabolism may play a role in olfactory transduction. The hypothesis to be tested is that specific phospholipid levels are rapidly and transiently changed in olfactory receptor neurons (ORNs) as the result of odor-dependent activation of PI3K. The proposed strategy is to characterize the PI3K(s) expressed in ORNs and assess PI3K activation by monitoring odor-evoked changes in the levels of two PI3K dependent phospholipids, PIP2 and PIPS, first in an established invertebrate animal model, and then to extend the results to mammalian ORNs. If, as preliminary findings suggest, PI3K signaling inhibits the output of mammalian ORNs in an odor-specific manner, the proposed research project has the potential to make a fundamental contribution to our understanding of the sense of smell. It could establish a cellular substrate for a bipolar basis to coding olfactory information and aid in explaining how odors not only excite but also inhibit ORNs. By creating a more complete understanding of the signaling pathways involved in the response to odors, this project will further elucidate both the normal and dysfunctional olfactory processes that are important to our quality of life and health.